1. Field of the Invention
This invention relates to compositions and methods for preventing or treating Plasmodium falciparum malaria. In particular, this invention relates to surfactant compositions and methods for reversing malarial resistance to quinoline antimalarials.
2. Description of the Prior Art
Plasmodium falciparum malaria is the world's most important parasitic infection accounting for an estimated 300 to 500 million cases and 1.5 to 2.7 million deaths annually [reviewed in Kain, 1998a]. P. falciparum infection accounts for over 90% of the morbidity and mortality associated with malaria. Young children living in malaria-endemic areas and other non-immune individuals are at the greatest risk of developing severe complications such as cerebral malaria leading to death. Despite intensive research, no specific treatments have been identified to prevent or improve the outcome of patients with severe malaria [White, 1998]. Severe and cerebral malaria carries a high fatality rate (>15%) even for young, previously healthy individuals [White 1998]. With escalating drug resistance and the lack of an effective vaccine, there is an urgent need for alternative therapeutic strategies.
Malaria associated morbidity and mortality is increasing because of widespread resistance to chloroquine, which is one of the safest and least expensive antimalarials. Chloroquine-resistant P. falciparum malaria was first recognized over 40 years ago and has since spread to almost all malaria-endemic areas [Su, 1997]. Chloroquine-resistant malaria has extended into the high transmission areas of Africa resulting in a public health crisis since switching to alternative antimalarials, such as mefloquine, artemisinin derivatives, halofantrine or quinine, is economically untenable for many countries in sub-Saharan Africa. Recent reports indicate that escalating mortality due to widespread malaria resistance is now taking place [Marsh, 1998].
The mechanism of chloroquine-resistance in P. falciparum remains controversial. However, it is frequently compared to multidrug resistance in mammalian cells that is often mediated by P-glycoproteins [Bray, 1998]. Mammalian P-glycoproteins are intrinsic membrane protein drug transporters that actively pump a wide variety of drugs and other xenobiotic compounds out of cells. Although P-glycoproteins can pump many types of chemotherapeutic agents like vinblastine and adriamycin out of cancer cells, the multidrug resistance phenotype of such cells can be modified by a variety of compounds including the immunosuppressant, cyclosporin A and calcium channel blockers such as verapamil. These chemosensitizers, competitively interact with drug-binding sites on P-glycoprotein, thereby interfering with the transport of chemotherapeutic agents out of cells.
It is known that drug resistance in P. falciparum can be reversed by calcium channel blockers such as verapamil [Martin. 1987]. The antipsychotics (e.g. chlorpromazine [Basco. 1992]), and histamine (H-1) receptor antagonists (e.g. promethazine [Oduola. 1998], chlorpheniramine [Basco, 1994]) also reverse chloroquine-resistance in P. falciparum in vitro and in malaria animal models [Bray. 1998]. However, these agents are pharmacologically active compounds with multisystem effects that result in a variety of undesirable side effects. Furthermore, these compounds are often more expensive than chloroquine itself and the concentrations required to reverse clinical drug-resistance for some of these agents can be toxic.
Accordingly, there is a need for safe, stable and inexpensive compositions and methods which reverse resistance to malarial quinoline.